Genome Editing as a Vehicle to Drive Successful Chimeric Antigen Receptor T Cell Therapies to the Clinic

Chimeric antigen receptor (CAR) T cells have emerged as an effective therapy for patients with relapsed and refractory haematological malignancies. However, there are many challenges preventing clinical efficacy and thus broader translation of this approach. These hurdles include poor autologous T cell fitness, manufacturing issues and lack of conserved tumour-restricted antigens to target. Recent efforts have been directed toward incorporating genome editing technologies to address these challenges and develop potent CAR T cell therapies for a diverse array of haematopoietic cancers. In this review, the authors discuss gene editing strategies that have been employed to augment CAR T cell fitness, generate allogeneic ‘off-the-shelf’ CAR T cell products, and safely target elusive myeloid and T cell cancers that often lack appropriate tumour-specific antigens.

Pasteurella multocida Endocarditis with Septic Arthritis: Case Report and Review of the Literature

Background: There is a paucity of evidence regarding optimal management of Pasteurella spp. endocarditis. The authors report the first case of Pasteurella spp. endocarditis with septic arthritis and review the literature. Case Description: A 79-year-old patient with significant comorbidities, including prosthetic aortic valve, was admitted with left knee swelling, fever, and confusion, having been scratched by a cat 2-weeks prior. At presentation, there was a metallic click, a Grade 3 pan-systolic murmur and Grade 1 flow murmur audible on auscultation. Blood and synovial fluid cultures both isolated Pasteurella multocida, identified by matrix-assisted laser desorption ionisation–time of flight, which was sensitive to penicillin according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST); minimum inhibitory concentration: 0.094). The patient underwent joint washout and received intravenous piperacillin/tazobactam for 3 days before switching to benzylpenicillin once sensitivities were known. Due to continued pyrexia, a transthoracic echocardiogram was obtained, which revealed a small mobile mass on a thickened mitral valve suspicious for a vegetation. On review by the Infective Endocarditis team, conservative management was deemed best, given the presence of comorbidities. Despite requiring further joint washout due to persistent knee pain, the patient was successfully treated with 8 weeks of antibiotic therapy (24 days of benzylpenicillin monotherapy, 2 weeks of benzylpenicillin and ciprofloxacin, and 15 days ciprofloxacin monotherapy). Discussion: Previous literature reviews report a higher mortality of Pasteurella spp. endocarditis when managed without cardiac surgery, thus recommending surgery in all cases. The authors found these to have confounding factors, including inadequate duration of antimicrobials, aortic root abscess, and rapid progression to death. The authors’ case of Pasteurella spp. endocarditis, complicated by septic arthritis, showed successful therapy without cardiac surgery.

The Safety of Medications During Pregnancy and Lactation in Patients with Inflammatory Rheumatic Diseases

The advances in treatments, including disease-modifying anti-rheumatic drugs and biologic agents, have significantly improved the management of inflammatory rheumatic diseases, allowing females with severe disease to become pregnant and lactate, previously considered as prohibited. Maintaining low disease activity with medications known to be safe from pre-conception to post-partum is a key point in reducing adverse pregnancy outcomes. Numerous observational and case studies have provided a growing amount of evidence on the use of safe anti-rheumatic medications in patients during pregnancy and lactation. Based on this information, this review discusses the safety of medications for patients with inflammatory rheumatic diseases during pregnancy and lactation. Among these, hydroxychloroquine, sulfasalazine, azathioprine, low-dose glucocorticoids, and low-dose aspirin are considered compatible with pregnancy, while methotrexate, cyclophosphamide, mycophenolate mofetil, and leflunomide are contraindicated. Non-steroidal anti-inflammatory drugs are only recommended for use early in pregnancy, as they are reported to cause rare but serious kidney problems in the fetus after 20 weeks or later. Cyclosporin, tacrolimus, and anti-TNF agents can be continued throughout pregnancy if the benefit is greater than the potential risk for the individual patient. Physicians should carefully weigh the risks and benefits of medications in patients with inflammatory rheumatic diseases considering pregnancy.

The Association Between Hypermobility Ehlers–Danlos Syndrome and Other Rheumatologic Diseases

Research has shown hypermobility Ehlers–Danlos syndrome (hEDS) to be associated with some complicated rheumatologic disease. In this feature paper, the authors discuss the prevalence and pathophysiology of rheumatologic conditions, specifically ankylosing spondylitis and rheumatoid arthritis, in patients with hEDS. Furthermore, the authors discuss possible reasons for the association of hEDS with these rheumatologic diseases.

Cannabinoids in the Treatment of Epilepsy: A Review

Cannabinoids have been studied for their role in the treatment of epilepsy for many years. The U.S. Food and Drug Administration (FDA) approved them for the treatment of some refractory syndromes in 2018. Cannabidiol and tetrahydrocannabinol are the most commonly studied cannabinoids and have been studied in great depth vis-à-vis their pharmacokinetics and pharmacodynamics. Studies have shown the efficacy of cannabinoids in the treatment of refractory epilepsy. A substantial amount of research has been performed exploring the interactions between cannabinoids and other conventional antiseizure medications. The exact mechanisms by which cannabinoids exert their effects on seizure control remain unclear and research into these mechanisms continues in great earnest. Cognitive changes from cannabinoids are constantly being studied and add to potential benefits from the use of these compounds. Cultural and social misconceptions and roadblocks about the use of cannabinoids persist and represent an ongoing obstacle to increasing research and therapeutic use of these compounds. This review focuses on all these aspects and of the use of these cannabinoids in the treatment of epilepsy and seeks to offer a fairly comprehensive description of the facets of cannabinoid therapy for refractory epilepsy.

A Case of Severe COVID-19 Infection in a Patient with Acute Myeloid Leukaemia: Critical Care Management and a Review of the Literature

Acute myeloid leukaemia (AML) is a highly heterogeneous disorder and is characterised by the proliferation of poorly differentiated myeloid cells due to underlying mutation, eventually causing bone marrow failure. Accounting for approximately 25% of cases, AML is the most frequent form of leukaemia in the world yet has the lowest survival rate among all leukaemias. Patients with haematological malignancy are more susceptible to severe acute respiratory syndrome coronavirus-2 infection and further development of severe infection, including pneumonia with poor blood oxygenation. The management of such patients is more challenging than expected. Successful management of one such case is discussed in this report. COVID-19 infection can cause great harm to a patient with underlying leukaemia and increase the mortality risk. It has a major impact on the physical and psychological health of the patient. Therefore, these patients need special care and attention. The authors emphasise the importance of supportive management (oxygen with bilevel positive airway pressure, prone positioning, and physiotherapy) to prevent complications.

Cardio-Metabolic Benefits of Walnuts in Type 2 Diabetes Mellitus: A Literature Review

Diabetes and its complications are main causes of morbidity and mortality among adults in the USA. An increase in the number of individuals with diabetes is primarily attributed to changes in dietary patterns including increased consumption of obesogenic foods and beverages. Many individuals who are overweight and obese show signs of insulin resistance and are at increased risk of Type 2 diabetes mellitus (T2DM) and cardiovascular disease. Lifestyle interventions (i.e., physical activity and nutrition) are the cornerstone of T2DM management and prevention. Prior research attests to the health benefits of consuming nuts, which have a substantial amount of mono- and polyunsaturated fatty acids, for individuals at risk for or with T2DM, and walnuts appear to be particularly promising. Walnuts are rich in nutrients, minerals, antioxidants, and vitamins that can contribute to improved cardio-metabolic risk factors in individuals at risk for or with T2DM. This review assesses the cardio-metabolic benefits of walnuts in T2DM. The authors’ review indicates that the reported effects of walnuts on glycaemic control have been inconclusive, with several studies showing association with improved glycaemic control while others show no effect. Despite their high energy density and potential to contribute to weight gain, the authors’ review suggests that walnuts can contribute to satiety without association with weight gain. This review also suggests that walnut consumption has been associated with improved low-density lipoprotein cholesterol levels and endothelial function but has not been associated with blood pressure improvement. Meta-analyses are warranted to quantitatively assess impact of walnut consumption on these cardio-metabolic risk factors in T2DM.

The Role of Confocal Endomicroscopy in the Diagnosis and Management of Pancreatic Cysts

Pancreatic cystic lesions are an increasingly common clinical finding. Current diagnostic techniques cannot reliably differentiate patients with high-risk lesions requiring surgical resection from those that can be safely surveyed or discharged. As a result, some patients may undergo unnecessary surgery with associated morbidity while others enter long-term surveillance with associated healthcare costs. Needle-based confocal laser endomicroscopy enables real time microscopic examination of the epithelial lining of a cyst wall at the time of a standard endoscopic ultrasound examination. The procedure is associated with low rates of adverse events, especially when the probe is loaded into the fine-needle aspiration needle before the procedure and examination times are limited. Needle-based confocal laser endomicroscopy has consistently been shown to have better diagnostic accuracy than cytology, which is often paucicellular and non-diagnostic in pancreatic cystic lesions. Studies have shown that diagnostic accuracy in needle-based confocal laser endomicroscopy is 84–95% in mucinous lesions and 39–99% in serous lesions. However, this technology is expensive and its place in diagnostic algorithms remains uncertain. Despite this, health economic analyses in certain health systems have been favourable, largely because of its potential to be able to discharge patients with benign lesions, such as serous cystic neoplasms, from long-term surveillance. Widespread adoption of this technology is unlikely but it has the potential to have an important role in indeterminate pancreatic cystic lesions.

Liver Transplantation in Patients with Acute-onChronic Liver Failure: Challenging the Limits

Acute-on-chronic liver failure (ACLF) is one of the main causes of death on the waiting list. Liver transplantation (LT) is the only curative treatment for patients with ACLF and therefore it should be considered in all cases. However, the applicability of LT in patients with ACLF is challenging, given the scarcity of donors and the high short-term mortality of these patients. Organ allocation has traditionally been prioritised according to the model for end-stage liver disease (MELD) system. However, the accuracy of MELD score is limited in patients with ACLF. In this article, the authors review the outcomes of patients with ACLF before and after LT, highlighting its clinical course, the feasibility of LT in the sickest patients, the role of the organ allocation system, and possible indicators of futility.

A Case Report of Extensively Drug Resistant Typhoid in Karachi, Pakistan: A Major Health Concern to Curb the Outbreak

The disease burden of extensively drug resistant typhoid in developing countries is a major emerging issue that cannot be ignored. Since its emergence from multidrug strains, the majority of typhoid cases in Karachi, Pakistan, have been extensively drug resistant, mostly infecting younger patients. In the study, the authors analysed one such case in an adolescent male and discussed how, by the implementation of national health policies, the spread of these infectious diseases could be prevented and the overall burden on the healthcare system decreased in areas with already limited resources.